ARSENITE (III) TREATMENT OF PROSTATE CANCER CELLS INCREASES HEDGEHOG SIGNALING

picture of Jordan Jimmie presenting his/her poster: ARSENITE (III) TREATMENT OF PROSTATE CANCER CELLS INCREASES HEDGEHOG SIGNALING

Jordan Jimmie , Ronald Heimark Ph.D.

ARSENITE (III) TREATMENT OF PROSTATE CANCER CELLS INCREASES HEDGEHOG SIGNALING

Chronic high arsenic exposure in drinking water has been discovered to be a carcinogen for the urogenital system. The hypothesis to be tested is that an important mechanism of arsenic toxicity is its ability to alter prostate carcinoma differentiation through altering the normal regulatory mechanisms of tumor suppressor genes.  In the region of Northern Arizona, including the Colorado Plateau and Verde Valley, residents deal with groundwater sources containing high levels of arsenic; these deposits originate from both geologic formations and past mining activities. The goal of our study was to investigate how signaling pathways are affected by arseniteIII (AsIII) exposure. We found that AsIII treatment of  a differentiated prostate cancer cell line, that the tumor suppressor PTEN was down regulated over time. We looked at the hedgehog signaling pathway and target genes that are important or cell proliferation since these factors play an important role in development and progression of prostate cancer. We used the Du145 cell line model for our studies. We treated Du145 cells with or without 5 μM AsIII, and then measured PTEN mRNA expression every two weeks for up to 18 weeks. Next, we measured hedgehog activity by transfecting Du145 cells, treated in 5μM AsIII and untreated, with a Gli-luciferase reporter plasmid in order to record Hedgehog signaling. This reporter is responsive to activation of Gli protein including Gli1, Gli2, and Gli3 which are zinc finger transcription factors. Data supports that cells treated with 5μM AsIII showed higher activity of Gli-luciferase, indicating increased Hedgehog signaling pathway expression. Arsenite treated Du145 cells showed increased expression of Patched1 and Gli2 mRNA. Two different pathways have been shown for the activation of hedgehog signaling. We propose that AsIII activation of the Hedgehog pathway is not through the canonical  Smoothened-dependent signaling pathway, but a non-canonical  pathway where loss of PTEN leads to activated Akt which results in the phosphorylation of Gli1. This work is significant because it establishes research between cancer biology and hydrology. Relating the two field allows for further research to be conducted linking our environment with public health. This research was supported by the “Native American Cancer Prevention” U54 grant from the NIH.

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